U.S. Pat. No. 4,105,776 to Ondetti et al discloses certain proline derivatives which includes captopril, an orally active angiotensin-converting enzyme (ACE) inhibitor, which is widely used for the treatment of hypertension, heart failure and other cardiovascular conditions. Captopril is generally available in the form of tablets which, as indicated in the Physicians' Desk Reference (PDR) 47th Edition, 1993, page 2358, is administered in a dose of from 25 to 150 mg, two or three times daily.
A once-daily captopril oral formulation would be a significant advantage over the PDR formulations for improving patient's compliance.
A variety of approaches are available for the development of prolonged release oral dosage forms. Such approaches include the use of polymers as fillers or coatings in preparing tablets, capsules, pellets, matrices (swellable or erodible) and the like. Many of these approaches have been tried in developing once daily captopril formulations with only limited success. Most recently, efforts have been directed towards investigating the colonic absorption of captopril utilizing a pulsatile drug delivery system (I. R. Wilding et al, Gastrointestinal Transit and Systemic Absorption of Captopril from a Pulsed-Release Formulation. Pharm. Res., Vol. 9, No. 5:654-657 (1992)). However, prolonged plasma levels of captopril suitable for once-a-day administration of captopril could not be obtained from these studies. Wilding et al disclose that a good percentage of captopril is probably absorbed from the upper GI tract (stomach and proximal small intestine) which explains the initial burst in the blood concentrations (high C.sub.max at a short T.sub.max). The drop in captopril blood concentrations that follows may be attributable to the changes in pH in the distal portions of the GI tract. Other factors such as metabolism, interaction with ingested food, and dilution of the drug at the absorption site may also play a role. (M. Hue et al, Passive and Carrier-mediated Intestinal Absorption Components of Captopril. J. Pharm. Sci. 77:1007-1011 (1988), S. M. Singhvi et al, Effect of Food on Bioavailability of Captopril in Healthy Subjects. J. Clin. Pharmacol. 22:135-140 (1982)).
Recently, a new prototype dosage form was developed by Seta et al, whereby an oily semisolid dosage form was used to deliver captopril to humans. This system was, however, capable of delivering captopril as a twice-a-day only. This dosage form also contained ascorbic acid as an antioxidant to improve the stability of captopril. (Y. Seta et al, Design and Preparation of Captopril Sustained-release Dosage .Forms and their Biopharmaceutical Properties. Int. J. Pharm. 41:245-254 (1988); Y. Seta et al, Preparation and Pharmacological Evaluation of Captopril Sustained-Release Dosage Forms Using Oily Semisolid Matrix. Int. J. Pharm. 41:255-262 (1988); Y. Seta et al, Design of Captopril Sustained-Release Preparation with Oily Semisolid Matrix Intended for Use in Human. Subjects. Int. J. Pharm. 41:263-269 (1988)).
U.S. Pat. No. 5,028,432 to Chopra and Makadia (Jul. 2, 1993) discloses a pharmaceutical composition in the form of a gelatin capsule which contains ranitidine as the active-ingredient and a non-aqueous matrix containing at least one fatty acid glyceride and/or mineral oil or paraffin and preferably at least one surfactant. The fatty acid glyceride will preferably be formed of a mixture of two oil excipients, one of which is a mixture of glycerides of medium chain (C.sub.8 -C.sub.10) fatty acids (such as Miglyol 812, Dynamit Nobel Co.), and the other of which is a mixture of glycerides of long chain (C.sub.12 -C.sub.18) fatty acids such as Gelucire.RTM. materials (Gattefosse Corporation).
Sheen et al, Bioavailability of a Poorly Water-Soluble Drug From Tablet and Solid Dispersions in Humans, J. Pharm. Sci., Vol. 80, No. 7, July 1991, pp 712 to 714, disclose the use of Gelucire 44/14-polyethylene glycol (PEG) 400 mixture as a carrier for REV 5901 (.alpha.-pentyl-3-(2-quinolinylmethoxy)benzenemethanol, a 5-lipoxygenase inhibitor) in a tablet. REV 5901 is a water-insoluble drug and the Gelucire 44/14-PEG 400 mixture provided improved dissolution thereof to effect faster release.
It is also known that Gelucire.RTM. materials have been employed in the following marketed products:
Solufen 200 by SMB Galephar (worldwide)
Zenium 4.5 by SMB Galephar (Europe)
Memoxy 4.5 by SMB Galephar (Europe)
Isorday 40 by Tillotts (Switzerland)